Ex vivo purging techniques have shown limited success for autologous bone marrow or stem cell transplantation in patients with leukemia or other malignancies. One goal of purging bone marrow or peripheral blood progenitor cells (PBPC) is to remove neoplastic cells while having little effect on normal stem cells and hematopoeitic progenitor cells. Transplantation of the purged marrow occurs after myeloablative therapy such as high dose chemotherapy or radiation [see for example, Stuart R. K., 1993, Semin. Oncol. 20(5 Suppl 6):40–54); Hammert L. C. and Ball, E. D., 1997, Curr Opin Hematol 4:423–428; Schneidkraut M. J., et al., 1996, J Hernatother 5:631–646]. Transplantation of any neoplastic cells with the marrow places the patient at risk for relapse of the malignancy (see for example, Rummel SA and Van Zant G, 1994, J. Hernatother. 3:213–218; Kvalheim G. et al, 1996, J Hernatother. 5:427–436). Methods undergoing current study to selectively kill neoplastic cells include the use of chemotherapeutic agents (such as 4-hydroperoxycyclophosphamide; see for example, Bird J. M., 1996, Bone Marrow Transplant, 18:309–313), monoclonal antobodies (see for example, Hammert, L. C. and Ball E. D., 1997, Blood Rev., 11:80–90), photodynamic therapy (see for example, Villeneuve L., 1999, Biotechnol Appl. Biochem.30:1–17), and viral vectors such as adenovirus (see for example, Hirai M, et al., 1999, Acta Haematol., 101:97–105; Marini F. C., et al., 1999, Clin. Cancer Res., 5: 1557–1568). However, recent experiments demonstrated that viable cancer cells remained in the bone marrow or PBPC after therapeutic purging leading to relapse of the malignancy. Another major limitation of current methods of ex vivo purging is the delayed engraftment due to damage to normal stem cells and/or early hematopoietic progenitor cells (Rummel SA and Van Zant G. 1994, J. Hernatother. 3:213–218, Damon et al., 1996, Bone Marrow Transplant, 17:93–99). Progenitor cells that are actively proliferating are consequently very sensitive to killing by most chemotherapeutic agents including 4-hydroperoxycyclophosphamide. The resultant loss of early progenitor cells causes a prolonged neutropenia and/or thrombocytopenia which places the patient at increased risk for life-threatening infection and/or bleeding. A tumor cytotoxic or cytolytic agent that spares normal hematopoietic cells is an important advance in cancer therapy.
In addition to neoplastic cells, bone marrow or peripheral blood progenitor cell harvests can include other undesirable cells such as autoimmune cells in people with arthritis or multiple sclerosis, for example. Other undesirable cells include those that mediate graft-versus-host disease (e.g., certain T-lymphocytes) in allogeneic transplants. Reduction or elimination of such undesirable cells would be an important in the treatment of cancer and autoimmune diseases.
PCT applications by Roberts et al. (WO/9918799 and PCT US98/21230) relates to the treatment of neoplasms with viruses.